Epilepsia, 32(2):279-283, 1991 hven Press, Ltd., New York 0 International League Against Epilepsy

Clinical Effects of Allopurinol on Intractable Epilepsy Hiroshi Tada, Keiichi Morooka, Kiyoshi Arimoto, and Takiko Matsuo First Department of Pediatrics, Toho Universify School of Medicine, Tokyo, Japan

Summary: We studied the clinical efficacy of allopurinol as add-on therapy in 31 patients with intractable epilepsy. When administered for a short time, allopurinol was effective in 17 patients (55%); 8 were seizure-free, 8 had 75% decrease in seizure frequency, and I had >50% decrease. Allopurinol was most effective in patients with localization-related epilepsy, especially in secondarily generalized tonic-clonic seizures. Allopurinol was not as effective in patients with Lennox syndrome or West syndrome, or in severe myoclonic epilepsy in infants. When allopurinol was administered > 1 year, its initial effective-

ness continued in 8 of 14 patients who exhibited initial improvement. In 2 of the remaining 6 patients, the initial improvement disappeared during the course of treatment but control was regained by increasing the dosage of allopurinol. Mild side effects were observed in 4 patients (13%): drowsiness in 3 and abdominal pain in 1. Allopurinol may be a useful antiepileptic drug (AED), and a double-blind placebo-controlled trial should be performed. Key Words: Epilepsy-Anticonvulsants-Allopurinol-Serotonin-Quinolinic acid-Kynurenine.

Coleman et al. (1974) first reported use of allopurinol, a xanthine oxdase inhibitor, to treat epilepsy in hyperuricosuria patients. DeMarco and Zagnoni (1986) first reported that allopurinol was effective in patients with intractable epilepsy without hyperuricosuria. After our initial report on the usefulness of this drug (Tada et al., 1988), we studied a larger number of patients.

rhage in 2, tuberous sclerosis in 2, familial in 1, and unknown in 10. The frequency of attacks varied from 1 a month to 50 a day (mean 2.4 a day). Of our patients, 90% had received more than two AEDs (one in 3 patients, two in 7 patients, three in 13 patients, four in 2 patients, five in 5 patients, and six in 1 patient). Duration of the baseline observation period depended on seizure frequency: 1 week in patients with more than one seizure a day, 2 weeks in patients with one to six seizures a week, and 2 months in patients with one to three seizures a month. Allopurinol was added to the existing treatment at an initial dosage of 3-10 mglkgiday administered three times daily. If clinical efficacy was not achieved, the initial dosage was increased until either sufficient effect was gained, side effects appeared, or the dosage reached 15 mglkglday. Efficacy was classified into five grades: grade 1 , complete disappearance of seizures (controlled); grade 2, decrease in seizure frequency by >75%; grade 3, decrease by

SUBJECTS AND METHODS

Thirty-one epileptic patients (17 males and 14 females) with more than one epileptic seizure a month despite administration of antiepileptic drugs (AEDs), were studied. Informed consent was obtained from all parents. The mean age was 7 years 10 months (range 4 months to 22 years). The mean age at epilepsy onset was 2 years 5 months (range 0 months to 14 years). The mean duration after epilepsy onset was 4 years 5 months (range 2 months to 22 years). Of the 31 patients, 26 (84%) were symptomatic, with central nervous system (CNS) manifestations such as cerebral palsy, mental retardation or minimal brain dysfunction. Etiologies were varied: perinatal abnormalities in 9, prenatal abnormalities in 4, CNS infection in 3, intracranial hemor-

TABLE 1. Therapeutic efficacy of allopurinol Status

n (%I

Controlled Reduction > 75%

8 (26) 8 (26) 1 13) 1 1 (36) 2 (6) 1 (3)

> 50%

Unchanged Worsened Others

Received April 1990; revision accepted October 1990. Address correspondence and reprint requests to Dr. H. Tada at 5-21-16, Ohmori-Nishi, Ohtaku, Tokyo, Japan.

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H . TADA ET A L .

280

TABLE 2. Therapeutic efjcacy with regard to classijcation of epilepsy Reduction Classification

n

Controlled

>75%

>50%

Unchanged

Worsened

Localization-related epilepsy NTLE TLE Generalized West syndrome Lennox syndrome SME

22 20 2 7 I 6 1

8 6 2 -

6 6 -

1

5 5

2 2 -

1

-

-

2

-

5 1

-

2 -

4 I

-

TLE, temporal lobe epilepsy; NTLE, non-TLE; SME, severe myoclonic epilepsy in infants.

In 10 patients, the initial dosage was increased because of insufficient effect; in 5 of the 10 patients, seizure frequency decreased after dosage increase (in 3 patients, seizures were controlled). Therefore, we consider this therapy to be dose dependent. Mild side effects were observed in 4 patients (13%): 3 had drowsiness and 1 had abdominal pain. We examined the type of epilepsy (Table 2) or type of seizure (Table 3). Allopurinol was most effective in localization-related epilepsy, especially in temporal lobe epilepsy; 15 of 22 patients (68%) responded to allopurinol. In Lennox syndrome, seizures were reduced by >75% in only 2 of 6 patients and were not controlled in any patient. Allopurinol was not effective in the 1 patient with West syndrome or in the 1 patient with severe myoclonic epilepsy in infants. Allopurinol was most effective in control of generalized tonic-clonic seizures, which disappeared or decreased in 6 of 8 patients (75%). Complex partial seizures disappeared or decreased in 10 of 16 patients (63%). Allopurinol was effective in only 2 (29%) of the 7 patients with minor seizures (tonic, myoclonic, and atypical absence seizures). Changes in seizure frequency in the 17 allopurinol-effective patients are shown in Fig. 1 . In most patients, seizure frequency decreased maximally within 2 weeks; in 2 patients, seizure frequency decreased gradually, reaching maximum decrease in >3 months. In patients exhibiting complete seizure

>50%; grade 4,49% decrease or increase of seizure frequency (unchanged); and grade 5, >50% increase in seizure frequency (worsened). We categorized grades 1, 2, and 3 as effective. We evaluated the effects of allopurinol at 1 week after reaching the final dosage if the patient had more than one seizure a day, at 2 weeks if the patient had one to six seizures a week, and at 2 months if the patient had one to three seizures a month. We evaluated the following factors to determine the influence on efficacy: classification of epilepsy and the seizure type, changes in seizure frequency, final dosage, clinical findings, serum uric acid concentrations, and AED plasma concentrations. Tests were performed before and 1 month after allopurino1 was started. Statistical analyses were performed using Student’s t test or chi-square test, including Yates correction.

RESULTS Immediate response Allopurinol was effective in 17 patients (55%) (Table 1). Seizures were completely controlled in 8, decreased by >75% in 8, and decreased by >50% in 1 patient. Seizure frequencies were increased in 2 patients and returned to previous levels after allopurinol was discontinued. In 1 patient who had both akinetic and tonic-clonic seizures, the former disappeared but the latter increased after allopurinol.

TABLE 3. Therapeutic efficacy with regard to seizure type Reduction Seizure type

(4

Controlled

>75%

>50%

Unchanged

Complex partial Tonic-clonic Tonic M yoclonic Atypical absence Infantile spasm Akinetic

(16) (8) (3) (3)

5 4 -

4 2

I -

5

-

-

1

-

-

Epilepsia, Vol. 32, N O . 2 , 1991

(1) (1) (1)

-

1 1

-

-

2 2 1 1

-

Worsened 1

2

ALLOPURINOL AND EPILEPSY

281

TABLE 5. Course of effective patients followed > I year

frequency of attack

Present status

Initial status Controlled --*

n=17

Reduced >75% Controlled Worsened --f

--f

Reduced >75%

(n)

Controlled

--f

--f

Worsened *

Reduced >75% Controlled by increase of allopurinol Increase in other AEDs

(2) (6)

(2) (4)

I

(8) 57% 14% 29%

fectiveness continued. In 2 patients, seizures reappeared during the clinical course but were controlled by increasing allopurinol dosage. We judged long-term effects of allopurinol as good in 10 of the 14 patients (71%). lweek

lmonth 3month Gmonth lyear after starting of this therapy FIG. 1. Changes in seizure frequency after allopurinol treatment.

control, seizures disappeared within 2 weeks in all patients. In the effective group, allopurinol dosages varied from 3.7 to 15.0 mg/kg. In 2 patients, seizure frequency increased with relatively low allopurinol dosages. In 3 of the 4 patients with side effects, allopurinol dosages were relatively low: 1 year. Mean follow-up period was 1 year 10 months (range 1 year to 2 years 5 months) (Table 5). In 8 patients (57%), early efTABLE 4. Comparison between allopurinol-effective and noneffective patients Clinical feature Age at time of study Age at onset Duration after onset More than five seizures a month No. of drugs No. with destructive brain lesion Serum uric acid (mg/dl) Change of uric acid (mg/dl)

Effective (n = 17)

Noneffective (n = 14)

Statistical difference

8yr4mo 3yr3mo 5yr2mo 53%

7 yr 10 mo 2 yr 10 mo 4 y r 2 mo 69%

NS NS NS NS

3.1 69%

NS NS

4.1

3.4

- 1.3

NS

- 1.9

2.9 47%

NS

DISCUSSION After the initial report of allopurinol efficacy in epilepsy (Coleman et al., 1974), additional patients were reported (Coleman et al., 1986), all with hyperuricosuria. DeMarco and Zagnoni (1986, 1988) initially reported the efficacy of allopurinol in “general” epilepsy in two-thirds of 64 patients with intractable epilepsy; they described its efficacy for various seizure types, especially tonic-clonic seizures. Subsequently, Sander and Patsalos (1988), Guzeva et al. (1988), and Aiko et al. (1989) reported uncontrolled clinical studies of efficacy (Table 6). All but Sander and Patsalos (1988) reported efficacy with intractable epilepsy. In rats, Mikhailov and Gusel (1983) reported decreased activity in penicillin-induced hippocampal epileptogenic foci. Thus, both clinical and research results suggest that allopurinol might be an effective AED. Based on review of the literature and our study, we conclude that allopurinol is most effective in localization-related epilepsies but is not effective in Lennox syndrome, infantile spasms, and severe myoclonic epilepsy in infants; generalized tonicclonic seizures were most responsive. From these results, we predict that allopurinol would be most effective in patients with localization-related epilepsy (especially temporal lobe epilepsy) with complex partial seizures or secondarily generalized seizures. Occurrence of side effects varied from 0 to 25% (Table 6), but when present were mild. Because the allopurinol dosages in our three patients with side effects were relatively low, variations in individual sensitivity are suggested. In 5 patients, seizure frequency was decreased after increase, suggesting a dose-dependent effect. The mechanisms of allopurinol action are not

Epilepsia, Vol. 32, No. 2 , 1991

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H . TADA ET AL.

TABLE 6. Literature

on allopurinol efficacy ~~

No. of patients Efficacy reduced >50% Unchanged (%) Worsened (%) Efficacy Seizure type Side effects

Coleman" et al., 1974, 1986

DeMarco and Zagnoni, 1986, 1988

Sander and Patsalos, 1988

3 100% -

64 67% 25 8

12 I00 -

GTC

Variable, most effective in GTC

(-1

(-1

Guzeva et al., 1988

Aiko et al., 1989

Present study

28 36%

I1 36%

55%

64 -

55

9 GTC

Headache 1 , diarrhea 1, malaise 1

(-1

Decreased appetite 2

31 36 6 GTC and CPS Drowsiness 2, abdominal pain 1

GTC, generalized tonic-clonic seizure; CPS, complex partial seizure. a Patients with hyperuricosuria.

completely known. Pharmacokinetic interactions are unlikely, because the AED plasma concentration in the patients of DeMarco and Zagnoni (1986, 1988), Aiko et al. (1989), and in our patients were virtually unchanged. A quinolinic acid mechanism hypothesis was postulated by Stober and Jacobi (1987) and DeMarco and Zagnoni (1987). Quinolinic acid, an intermediate product of the oxidative pathway of tryptophan into NAD, is a potent endogeneous neuroexcitatory substance (Lapin, 1980, 1981; Stone and Perkins, 1981; Schwarcz et al., 1984; Vezzani and Wu, 1988). Kynurenine also appears in the same pathway and has a neuroexcitatory effect (Gusel and Mikhailov, 1980; Lapin, 1980, 1981). Allopurinol inhibits tryptophan2,3,-deoxygenase (Becking and Johnson, 1967; Badawy and Evans, 1973), the key enzyme of the oxidation of tryptophan, and the anticonvulsant effect may be due to reduction of quinolinic acid and kynurenine. Mikhailov and Gusel (1983) also described elevated serotonin in rat brain after allopurinol administration and suggested that a shift in tryptophan metabolism toward increased serotonin production by allopurinol might inhibit development of penicillin-induced epilepsy in rats. An increase in brain serotonin may be a secondary phenomenon of the inhibitory effect of allopurinol on tryptophan2,3-deoxygenase. Allopurinol has also been postulated to inhibit xanthine oxidase, resulting in inhibition of hypoxanthine conversion to xanthine and accumulation of hypoxanthine. Because hypoxanthine may be an endogenous ligand of the benzodiazepine receptor (Skolnick et al., 1978), it may act as an anticonvulsant. This hypothesis seems unlikely because such an effect was obtained by extremely high concentrations owing to the high Ki of hypoxanthine to the benzodiazepine receptor (Saano, 1987). Epilepsia, Vol. 32, No. 2 , 1991

Because we have used allopurinol only as add-on therapy, we cannot exclude the possibility that anticonvulsant effects of allopurinol are achieved by interaction with other AEDs. A placebo-controlled double-blind study is needed, possibly as monotherapy, to determine whether allopurinol is truly an effective AED. REFERENCES Aiko H, Matsuoka S, Morimoto T, et al. The experience of administration of allopurinol on childhood intractable epilepsy (in Japanese), presented at the 31st annual meeting of the Japanese Child Neurology Society, Sapporo, Japan, 1989. Badawy AAB, Evans M. The mechanism of inhibition of rat liver tryptophan pyrrolase activity by 4-hydroxypyrazolo(3,4dpyrimidine (allopurinol). Biochem J 1973;133:585-91. Becking GC, Johnson WJ. The inhibition of tryptophan pyrrolase by allopurinol, an inhibitor of xanthine oxidase. Can J Biochem 1967;45:1667-72. Coleman M, Landgrebe M, Landgrebe A. Progressive seizures with hyperuricosuria reversed by allopurinol. Arch Neurol 1974;31:23&42. Coleman M, Landgrebe M, Landgrebe A. Purine seizure disorders. Epilepsia 1986;27:263-9. DeMarco P, Zagnoni P. Allopurinol and severe epilepsy. Neurology 1986;36:1538-9. DeMarco P, Zagnoni P. Allopurinol in severe epilepsy. A preliminary report. Neuropsychobiology 1988;19:51-3. DeMarco P, Zagnoni P. Allopurinol and epilepsy [reply from authors]. Neurology 1987;37:1691-2. Gusel WA, Mikhailov IB. Effect of tryptophan metabolites on activity of the epileptogenic focus in the frog hippocampus. J Neural Transm 1980;47:41-52. Guzeva VI, Gusel WA, Mikhailov IB. Allopurinol in the combined therapy of severe forms of epilepsy in children. Zh Nevropatol Psikhiatr 1988;88:6%72. Lapin IP. Effects of kynurenine and quinolinic acid on the action of convulsants in mice. Pharmacol Biochem Behav 1980; 13: 17-20. Lapin IP. Kynurenines and seizures. Epilepsia 1981;22:257-65. Mikhailov IB, Gusel WA. Pharmaco-dynamic mechanisms for reducing the activity of an epileptogenic focus with allopurinol. Zh Nevropatol Psikiatr 1983;83:870-3. Saano V. GABA-benzodiazepine receptor complex drug actions. Med Biol 1987;65:167-73. Sander JW, Patsalos PN. Allopurinol was an add-on drug in the management of intractable epilepsy. Epilepsy Res 1988; 2: 323-5.

ALLOPURINOL AND EPILEPSY Schwarcz R, Brush GS, Foster AC, French ED. Seizure activity and lesions after intrahippocampal quinolinic acid injection. Exp Neurol 1984;84:1-17. Skolnick P, Marangos P, Goodwin FK, Edwards M, Paul S . Identification of inosine and hypoxanthine as endogenous inhibitors of [3H]diazepam binding in central nervous system. Life Sci 1978;23:1473-80. Stone T, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharrnacol 1981;72:411-2. Stober T , Jacobi P. Allopurinol and epilepsy. Neurology 1987;37:1691. Tada H, Matsuo T, Arimoto K, Morooka K. The usefulness of allopurinol administration on intractable epilepsy (in Japanese), presented at the 15th annual meeting of Kantoh Childhood Epilepsy Society, Tokyo, Japan, 1988. Vezzani A, Wu HQ. Quinolinic acid-induced seizures, but not nerve cell death, are associated with extracellular Cazf decrease assessed in the hippocampus by brain dialysis. Brain Res 1988;454:289-97.

R6SUME Les auteurs ont CtudiC I’efficacitC clinique de I’Allopurinol comme mtdicament adjuvant chez 3 I patients prksentant une kpilepsie intraitable. Lors d’une administration de courte durCe, I’Allopurinola ttC efficace chez 18 patients (55%): 8 n’ont plus prksentt de crises, 8 ont prCsentt une diminution de 75% de la frtquence des crises, et 1 une diminution supCrieure B 50%. L’Allopurinol s’est surtout montrC efficace chez les patients prCsentant une tpilepsie en relation avec une localisation, surtout en cas de crises tonico-cloniques par gtnkralisation secondaire. L’Allopurinol n’a pas Ctt aussi efficace chez des patients prCsentant un syndrome de Lennox-Gastaut, un syndrome de West ou une tpilepsie myoclonique stvtre du nourrisson. Lorsqu’il a

283

CtC administrC pendant plus d’un mois, son efficacitt initiale s’est maintenue chez 8 des 14 patients arnCliorts au dtpart. Chez 2 des patients restants, I’amClioration initiale a disparu pendant la poursuite du traitement, mais un contrde a pu Ctre rtcuptrC par augmentation des doses. Des effets secondaires peu stvtres ont Ctt observes chez 4 patients (13%): baisse de la vigilance chez 3, douleurs abdominales chez 1. L’Allopurinol peut &re un mCdicament antikpileptique utile, et les auteurs recommandent la rtalisation d’essais en double-aveugle contre placebo.

(P. Genton, Marseille)

RESUMEN Hemos estudiado la eficacia cli’nica del allopurinol como terapia andida en 3 1 enfermos con epilepsia incontrolable. Cuando se administro durante un pen‘odo corto de tiempo, el allopurinol fue eficaz en 17 enfermos (55%); 8 no tuvieron ningun ataque, 8 tuvieron mostraron un 75% de reducci6n de la frecuencia de ataques y 1 tuvo mAs de 50% de reducci6n. El Allopurinol fue mas eficaz en enfermos con epilepsia relacionado con alguna localizacion y especilamente con epilepsia secundariamente generalizada con ataques-cl6nicos. El allopurinol no fue eficaz en enfermos con un sindrome de Lennox, un sindrome de West o en epilepsia miocl6nica severa en ninos. Cuando se administr6 durante mas de 1 ano la eficacia inicial continuo en 8 de 10s 14 pacientes que habian mostrado una mejorfa inicial. En 2 de 10s restantes 6 pacientes, la majoria inicial desapareci6 durante el curso del tratamiento pero se consiguid un nuevo control al incrementar la dosis. Se observaron signos de efectos de intolerancia ligeros en 4 pacientes (13%); mareo en 3 y dolor abdominal en 1. El allopurinol puede ser 6til con medicacidn antiepiltptica aunque se debe practicar un ensayo doble ciego controlado con placebo. (A. Portera-Sanchez, Madrid)

Epilepsia, Vol. 32, No. 2, 1991